Many current pharmaceuticals are very efficacious and potent, thus very small doses are needed to provide the desired benefit. This causes problems in formulation of the pharmaceutical into a consumer usable form. The difficulty is to devise a method to ensure that a consistent dose of the pharmaceutical is present in each tablet or other drug delivery form. A typical method for accomplishing this is to formulate tablets with a variety of additive agents to increase the size of a tablet to a usable size for consumers while optimizing the manufacturing process and the tablet end use properties. Classes of additives include fillers, binders, disintegrating agents, dissolving or solubilizing agents, lubricants, glidants, colorants, flavors, sweetening agents, and wetting agents. One difficulty associated with mixing a variety of powders into a single tablet is that if the particle sizes are different it can be difficult to achieve homogeneity of distribution of the various components in the final powder and therefore in the final tablet. This variation in the particle size of ingredients often results in the necessity of increasing the overage of the active drug ingredient in order to ensure a minimum potency in each and every tablet, resulting in additional amount and cost for the drug ingredient. Maintaining a small particle size reduces this variation.
Typical solubilizers include low melting polymers such as the poloxamer class of polymers. These polymers are block co-polymers of ethylene oxide and propylene oxide and have the advantage of being relatively low melting polymers with typical melting temperatures of from about 45 to 60° C. Thus, they are solid at room temperature, but melt readily at higher temperatures.
One way to ensure homogeneity of distribution of the various components in the final powder is to find a way to make all the powders have about the same particle size. Typically, the desired particle size is less than 200 microns and often less than 50 microns. The problem for the use of poloxamers is that their low melting temperature makes most milling practices impractical because the poloxamer either melts or is charred during the milling process. One solution has been the use of micro-milled poloxamer that is manufactured under cryogenic conditions, such as cooling the poloxamer to less than −70° C. then rapid milling. Preferably the milling is carried out at a temperature of less than −100° C. There are numerous problems associated with this solution the first being the cost to produce a micro-milled poloxamer. It requires the use of a cooling agent such as liquid nitrogen which is expensive. There is also a high labor component in part due to relatively low rates of production. The material must be warmed to avoid aggregation. The process is slow in part because it requires many steps. Finally, good manufacturing practices in the formation of pharmaceuticals require scrupulous attention to the detection and elimination of any potential contaminants. This is hard to do and costly with the cryogenic micro-milling process making it less desirable.
It would be desirable to develop a rapid, cost-effective process for formation of poloxamer particles that would enable them to be readily used in pharmaceutical formulations. Preferably the process will produce a high yield of the desired particles with minimal possibility of contamination from foreign material.